tbuckley/cabot-search huggingface dataset:
Analysis of concordance between microsatellite instability by next generation sequencing (NGS-MSI) and mismatch repair deficiency by immunohistochemistry (IHC-MMR) in &gt;28,000 colorectal tumors.
Authors: Rouba Ali-Fehmi, Matthew James Oberley, Harris Kraus, Thomas J Herzog, Anthony Karnezis, Emmanuel S. Antonarakis, Pashtoon Murtaza Kasi, Alex Patrick Farrell, Joanne Xiu, Jeffrey Swensen, David Spetzler, Jim Abraham, Wolfgang Michael Korn, David Bryant
Journal: Journal of Clinical Oncology (2023)

30 Background: The use of immune checkpoint inhibitors (ICI) in MSI-H/MMRd CRC patients has profoundly changed the treatment landscape in the metastatic setting; the most recent NICHE-2 trial showed 100% response rate in MSI-H/MMRd locally advanced CRC patients treated with neoadjuvant ICI, further highlighting the importance of identifying these patients accurately to enhance patient care. Here we report the concordance of NGS-MSI and IHC-MMR from a very large cohort of CRC tumors and study the molecular characteristics and clinical outcomes of these patients. Methods: A total of 28,105 CRC tumors were analyzed by NGS (592 genes, NextSeq or WES, NovaSeq) and IHC. MMRd was defined as complete loss of ≥1 IHC stains (MLH1, MSH2, MSH6, or PMS2) and proficient (MMRp) as any positive staining for all four proteins. MSI status was determined from over 7,000 target microsatellite loci covered by NGS. Central pathology review (CPR) of MMR IHC was done on 73 cases with discordant MMR/MSI results. Real-world overall survival was obtained from insurance claims and calculated from either tissue collection or treatment start to last contact; Kaplan-Meier estimates were calculated for molecularly defined patients. Results: For CRC tumors with NGS and IHC, 28031/28105 were concordant (99.74%), 0.09% were MMRd/MSS, and 0.2% were MMRp/MSI-H. After CPR, 23/24 (96%) of MMRd/MSS cases and 46/49 (94%) of MMRp/MSI-H were confirmed. Of the 46 post-CPR MMRp/MSI-H CRC samples, 52% had ≥1 pathogenic missense mutation in including MLH1/PMS2/MSH2/6 or MLH3, MSH3, PMS1 or POLE. Of the 23 post-CPR MMRd/MSS CRC samples, 38% had MLH1 loss, 91% PMS2 loss, no MSH2 loss and 9% MSH6 loss. When comparing clinical outcomes with concordant MSS/MMRp tumors, concordant MSI-H/MMRd patients had significantly longer OS (HR=1.131 [95% CI: 1.02-1.254], p&lt;0.001) and post-ICI survival (HR= 2.695 [95% CI: 1.932-3.76], p&lt;0.001). Compared to MSS/MMRd tumors (N=21), MSI-H/MMRp (N=29) trends to have longer OS (HR=2.163, [95% CI: 0.939-4.983], p=0.064) and insufficient ICI-treated patients were available for analysis. Conclusions: Here we report from &gt;28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy. [Table: see text]
A glimpse into the future of cholangiocarcinoma: Predicting the future incidence based on the current epidemiological data.
Authors: Sri Harsha Tella, Mikolaj Wieczorek, David Hodge, Amit Mahipal
Journal: Journal of Clinical Oncology (2023)

616 Background: Cholangiocarcinoma (CCA) is an aggressive, heterogenous group of neoplasms that arise from the epithelial lining of bile ducts that have dismal poor prognosis. A recent epidemiological study in the United States demonstrated a steady increase in the incidence of cholangiocarcinoma from 2001 to 2017 with a predominant increase in the intrahepatic sub-type (iCCA). We sought to evaluate the future incidence of cholangiocarcinoma stratified based on the subtype, age, sex, and race, that could possibly help plan prevention, control, and treatment strategies for this cancer. Methods: We obtained histologically confirmed cases of cholangiocarcinoma (ICD-0-3 Site: C220, C21, and C240) from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) 18 registries between 2000 to 2017 and predicted the incidence between the years 2018-2029. We applied age-period-cohort models to estimate future cholangiocarcinoma incidence rates (per 100, 000) and the estimated disease burden by multiplying incidence forecasts by corresponding US Census population projections. Results: A total of 12,737 and 8,395 patients with iCCA and extra-hepatic cholangiocarcinoma (eCCA) were included in the final analysis. The median age of iCCA cohort was 64 (range: 20-79) years and 46.4% were females whereas in eCCA the median age was 66 (range: 20-79) years and 43.8% were females. The overall observed age-adjusted incidence of iCCA between 2000-2017 was 1.07, which is predicted to increase to 2.13 by 2029 (99% increase) with a predominant increase in incidence rate observed in the age groups 70-79 and White males and females. Interestingly, incidence rate remained stable in Black and Asian males and in Asian females. Similarly, as compared to 2001-2017, the incidence of eCCA is projected to increase from 0.74 to 1.01 by 2029 (36.5% increase) with predominant increase noted in Black and Hispanic cohorts. In contrast, we noticed a relatively stable and decreasing incidence rate in White and Asian females, respectively. Conclusions: We predict an overall increased incidence of both iCCA and eCCA over the next decade especially in certain subgroups warranting the urgent need for preventive strategies. Further epidemiological studies are needed to determine the etiological factors contributing to predicted increase in incidence rate.
<i>KRAS </i>WT pancreatic adenocarcinomas: Another disease?
Authors: Imen Ben-Ammar, Michel Ducreux, Valérie Boige, Antoine Hollebecque, Anthony Tarabay, Cristina Smolenschi, Maximiliano Gelli, Marie Laure Tanguy, Marine Valery, Etienne Rouleau, Rémy Barbe, Alice Boileve, Alina Cristina Fuerea
Journal: Journal of Clinical Oncology (2023)

750 Background: KRAS mutation is the most common molecular alteration (MA) in pancreatic adenocarcinoma (PDAC), and only 8-10% of patients (pts) harbor KRAS wild-type tumors (WT). This study describes clinical and molecular features of KRAS WT PDAC and compares it to mutant KRAS (m KRAS) PDAC. Methods: A retrospective chart review of clinical/molecular data was performed on all pts with PDAC who had contributive molecular profile at Gustave Roussy. KRAS status was determined on tumor molecular profiling as part of routine care using an in-house panel or Foundation Medicine NGS either on tissue (63%) or liquid biopsy (37%). Results: Overall, 41 pts with KRAS WT PDAC were compared to 197 pts with mKRAS PDAC. Median OS (mOS) from initial diagnosis was significantly higher in the KRAS WT group compared to mKRAS group (32.8 months (mts), CI95% [25.9-NR] vs 21.5 mts, CI95% [18.8-24.9] respectively), as mOS from metastatic diagnosis, 26 mts, CI95% [15.7-NR] for KRAS WT pts vs 17.7 mts CI95% [15.5-19.3] for mKRAS (all p&lt;0.05)). After adjustment on gender, age, metastasis status at diagnosis, hazard ratio (HR) of OS from metastatic stage diagnosis associated with KRAS status was 1.9 [1.1;3.4], p=0.02 (similar for 1st line PFS and OS from initial diagnosis). MA were found in 31 KRAS WT pts (76%). KRAS WT and m KRAS pts harbored different molecular profiles with less alterations of TP53, SMAD4 and CDKN2A/B (p&lt;0.05) in KRAS WT tumors, but more of BRAF (p&lt;0.05), PALB2, RET and BRIP1 (p=NS) alterations. Interestingly, 3 MSI tumors were found in the KRAS WT group (one received immunotherapy), vs none in m KRAS group). Tumor mutational burden was similar (2.00 Mut/Mb in KRAS WT pts vs 2.7 Mut/Mb in m KRAS pts). Based on ESCAT classification, a putative therapeutic target (ESCAT I-IV, other than KRAS) was identified in 15 (36%) KRAS WT pts and 65 (33%) m KRAS pts, thus enriching the therapeutic panel for these patients. Indeed, for example 9 (22%) KRAS WT pts received an oriented therapy after palliative treatments (such as anti-RET or anti-PARPs) and showed higher survival rates compared to KRAS WT pts who did not (mOS from diagnosis in months NR (14.2; NR) and 28.3 (26; NR) respectively). Conclusions: In our cohort of 238 PDAC, we confirm that KRAS is a prognostic factor of OS. KRAS WT PDAC have a significantly longer OS compared to m KRAS. Moreover, 36% of KRAS WT PDAC pts had a potentially actionable MA, and 9 pts displayed higher survival rates after receiving oriented therapies. This study suggests that KRAS WT PDAC should be eligible for a large molecular screening.[Table: see text]
A single-arm, open-label, phase II study investigating anti-HER2 ADC plus anti-PD-1 antibody in patients with unresectable locally advanced or metastatic BTC with HER2 overexpression.
Authors: Xiaofeng Chen, Fen Guo, Xinyi Zhang, Jinrong Qiu, Tongsen Zheng, Hong Qiu, Yitong Tian, Lanlan Pan, Jiaguang Zhang, Yizhang Chen, Haoyang Shen, Chao Wang
Journal: Journal of Clinical Oncology (2023)

TPS619 Background: 1. Biliary tract cancer (BTC) accounts for 4% of all digestive tract cancers. In 2016-2020, the incidence of BTC has gradually increased worldwide. In China, gallbladder carcinoma accounted for 1.7% of all tumors and 1.9% of deaths in some regions. 2. The standard second-line treatment regimen is mFOLFOX, with an ORR of 5%, PFS of 2 months and OS of 6.2 months. Methods: This is a single-arm, open-label, phase II study, approximately 31 patients of unresectable locally advanced or metastatic BTC with HER2 overexpression will be enrolled. Each treatment cycle is 14 days. Therapeutic regimen: Disitamab Vedotin 2.5mg/kg IV, D1, Q2W + Zimberelimab 240mg IV, D1, Q2W All patients treated until a loss of clinical benefit or unacceptable toxicity is observed by the investigator. Objective: to evaluate the efficacy and safety of Disitamab Vedotin + Zimberelima in patients with unresectable locally advanced or metastatic BTC with HER2 overexpression Disitamab Vedotin: Vedecitumab is an antibody-drug conjugate (ADC), with a humanized antibody conjugated to four tubulin inhibitor molecules (DAR=4) Zimberelimab: Zimberelimab is a fully human IgG4 monoclonal antibody that specifically binds to PD-1 molecules on the surface of lymphocytes. This drug is approved for r/r cHL and is also effective in the cervical cancer. Clinical trial information: NCT05540483 .
Single-arm phase II trial to evaluate the safety of laparoscopic/robotic total gastrectomy with spleen-preserving splenic hilar dissection for locally advanced proximal gastric cancer that invades the greater curvature: JCOG1809.
Authors: Takahiro Kinoshita, Takaki Yoshikawa, Toshiyasu Ojima, Takeshi Omori, Haruhiko Cho, Michitaka Honda, Souya Nunobe, Yukinori Kurokawa, Shinji Kuroda, Junki Mizusawa, Haruhiko Fukuda, Narikazu Boku, Masanori Terashima
Journal: Journal of Clinical Oncology (2023)

TPS479 Background: The standard treatment for locally advanced proximal gastric cancer invading the greater curvature is “open total gastrectomy combined with splenectomy” (OTG+S) aiming for whole clearance of the splenic hilar lymph nodes. However, its pertinent postoperative severe complication (e.g. pancreatic fistula) is problematic. An objective of this study is to evaluate the safety of “laparoscopic or robotic total gastrectomy with spleen-preserving splenic hilar dissection” (LRSHD) as a new treatment option which has a potential to reduce surgical morbidity, subsequently to replace the current standard treatment, OTG+S. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria are as follows; clinical T2-4a resectable locally advanced proximal gastric adenocarcinoma that invades the greater curvature; without obvious lymph node metastasis at the splenic hilum nor direct invasion to the spleen/splenogastric ligament. Protocol treatment is laparoscopic or robotic total gastrectomy with splenic hilar lymph node dissection (D2 + No.10 lymphadenectomy according to the Japanese guidelines) in which the spleen is preserved with skeletonizing the splenic vessels. Quality control of surgery is assured by surgeon’s qualification and central peer review of intraoperative photo at the splenic hilum after dissection. The primary endpoint is the proportion of postoperative pancreatic fistula and/or intra-abdominal abscess formation with Clavien-Dindo Grade III or higher (within 30 days after surgery). Secondary endpoints are intraoperative blood loss, operation time, mortality, overall postoperative complication, number of yield splenic hilar nodes, number of metastatic splenic hilar nodes, conversion to splenectomy, conversion to laparotomy, relapse-free survival, and overall survival. Sample size was set as 85 patients to obtain 80% power considering that 15% of patients are judged as unresectable intraoperatively, with the hypothesis that the primary endpoint would have an expected value of 7% and a threshold value of 16% in one-sided alpha of 0.1. Planned accrual period is 5 years. The accrual began in August 2019. As of August 2022, 53 of the planned 85 patients (62.4%) have been enrolled. When the safety of LRSHD is proved by this study, a non-inferiority phase III trial will be consequently launched. Clinical trial registry number: UMIN000037580. Clinical trial information: UMIN000037580 .
Influence of clinical and tumor characteristics on survival in patients with hepatocellular carcinoma with bone metastasis.
Authors: Muhammet Ozer, Suleyman Yasin Goksu, Jesus C. Fabregas, Brian Hemendra Ramnaraign, Sherise C. Rogers, Thomas J. George, Ilyas Sahin
Journal: Journal of Clinical Oncology (2023)

525 Background: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the incidence of liver cancer is rapidly rising in the United States. Advanced HCC generally has a dismal prognosis with an expected survival of less than 1 year. Bone metastases from HCC are infrequent with a poorer prognosis. However, the factors influencing their survival are not well-understood. We aimed to study the effects of clinical and tumor characteristics on survival in HCC patients with bone metastasis. Methods: We selected adult patients with HCC who had bone metastasis diagnosed between 2004 and 2019 using the National Cancer Database (NCDB). We described baseline characteristics using percentages. We performed the Kaplan-Meier method to calculate the median overall survival (OS). We included demographics (age at diagnosis, gender, race, insurance status), comorbidity score, and treatment characteristics. Results: Of a total of 3301 HCC patients with bone metastasis, 87.1% were male, and 12.9% were female. Among all, 72.2% were white, 19.3% were black, and 8.5% were others. A total of 59.9% of patients were &lt;65 years. Eighty-six-point four percent of the patients had a total Charlton-Deyo comorbidity score of &lt;3 and 13.6% had it ≥3. Among patients with known tumor grade, 25.4% had well differentiated, 37.8% moderately differentiated, 35.4% poorly differentiated, and 1.2% undifferentiated tumors. In univariate analysis, patients with well-differentiated tumors had better OS compared to poorly differentiated tumors (5.4 mo vs. 3.3 mo, p&lt;0.05). In treatment groups, both single and multi-agent chemotherapy as first-course therapy significantly improved OS compared to patients’ chemotherapy was not administered (6.8 mo vs. 2.1 mo; 8.9 mo vs. 2.1 mo, respectively). We found no mortality difference between age, gender and race groups. Conclusions: In this cohort analysis of NCDB data, we report better OS in treatment receipt, lower tumor grade, and lower comorbidity score in HCC patients with bone metastasis. Previous studies of HCC patients with bone metastasis have been limited by small sample sizes, and lack of nationwide oncology outcomes data. Further large-scale prospective studies are needed.
Screening or symptoms? Colorectal cancer diagnosis in Uruguay.
Authors: Santiago Fontes, Megan Berry, Ana Marín-Jiménez, Juan Carlos Sánchez, Gabriel David Krygier, Mauricio Cuello
Journal: Journal of Clinical Oncology (2023)

71 Background: Colorectal cancer (CRC) remains a major health burden worldwide. Screening is employed due to its proven efficacy in reducing CRC incidence and mortality. In Uruguay, there is a longstanding National CRC screening program using fecal occult blood test (FOBT) as the preferred method. It is to be expected that patients with screen-detected CRC have better prognosis than those with symptoms due to earlier diagnosis and other favorable tumor/host characteristics. Beyond the well described earlier stage at diagnosis, other aspects have not been widely studied and data is sparse. An increasing proportion of CRC patients are diagnosed by screening rather than symptoms. Aim: We sought to establish and evaluate the correlation between clinicopathological features and TNM stage at diagnosis and diagnostic modality. Methods: A retrospective review of all newly diagnosed CRC patients from January 2008 to December 2021 was conducted by the authors. A total of 934 patients aged 50-80 years at diagnosis were included. Clinical, histological, diagnostic and treatment data was collected and findings were stratified and correlated according to screening detection vs symptomatic patients. Results: On one hand, 15% of patients had a positive FOBT leading up to their diagnosis. FOBT detected tumors presented a less advanced locoregional T-N staging (p = 0.001). Tumors were preferentially located in the proximal colon (33.1 vs 19.9%); p&lt;0.001. Stage I CRC was more frequently detected in subjects with positive FOBT (14.2%) than in individuals with symptoms (5.9%); p = 0.002. Conversely, detection rates for stage IV CRC were 17.7% and 26.7% respectively; p = 0.002. A higher percentage of stage III screened patients underwent adjuvant chemotherapy when compared to their symptomatic counterparts (97.7 vs. 85.0 %, p = 0.016). On the other hand, 793 patients (85 %) were diagnosed after onset of signs or symptoms. There was a preponderance of advanced-stage disease (stages III–IV 36-27% respectively). The most common symptoms reported were change in bowel habits (52%), abdominal pain (47 %) and bleeding (45%). The most common overall sign was anemia. One hundred eighty-two patients (22.5%) required an emergency surgery mainly for obstructive colon cancer. Conclusions: Despite equal access to colorectal cancer screening, in Uruguay diagnosis after development of symptomatic cancer remains more common. FOBT detected cancers presented less advanced clinicopathological characteristics and differing management that potentially could be driving a more favorable outcome. Mode of detection is therefore an important indicator that should be taken into account when defining risk assessment in treatment decisions. These findings also support the need for continued improvement and recruitment of patients into screening programs. It must be the focus for future initiatives.
A prospective translational study investigating the association of gut microbiome (GM) diversity with pathological complete response (pCR) after neoadjuvant treatment in early stage rectal and esophageal cancers.
Authors: Ronan Andrew Mc Laughlin, Ciaran Devoy, carolyn moloney, Kathleen Bennett, David Mcmahon, Michael R Conroy, Orla Fitzpatrick, Keith Egan, William Grogan, Oscar S. Breathnach, Patrick G. Morris, Adrian Gerard Murphy, Jarushka Naidoo, Mark Tangney, Bryan T. Hennessy
Journal: Journal of Clinical Oncology (2023)

TPS819 Background: The gut microbiome (GM) is thought to influence host immunity by modulating multiple immunologic pathways. Studies have suggested that dysbiosis of the GM confers a predisposition to certain malignancies and influences response to immune checkpoint inhibitors. However, little is known about how the GM diversity influences complete pathological response to neoadjuvant therapy in gastrointestinal (GI) tumours. We hypothesize that a more diverse GM constitution at baseline will lead to improved pathological response at the time of definitive surgery. Methods: We designed a cross-institutional multi-center translational study investigating the impact of the GM diversity on the efficacy of neoadjuvant therapy in GI cancers by assessing its association with pathological response. The study population will consist of patients with an early-stage rectal or esophageal cancer due to commence neoadjuvant therapy (including chemotherapy and chemoradiation) and planned for definitive surgery. Patients who received prior chemotherapy/monoclonal antibodies/immune checkpoint inhibitors or radiation will be excluded. The study assessments will include fecal sampling of the GM prior to neoadjuvant therapy, upon completion and again six months post completion of therapy. Fecal samples will be analysed by 16S RNA sequencing. Pathological response will be examined at time of surgery and patients will be classified as responders (complete pathological response) or non-responders. The primary endpoint of the study is to examine the association between the GM diversity and pathological response. 120 patients will be recruited over 18 months. Results: Species richness (Alpha Diversity) will be analysed using the Shannon diversity index and Jaccard similarity index to calculate beta diversity. Classification and clustering analysis will be performed with Principal Component Analysis (PCA) and Random Forest analysis. Comparison of taxa or functions between clinical cohorts will be performed using the two tailed Z test and corrected using the false discovery rate to determine Q-values. The association between GM and complete pathological response will be examined using logistic regression analysis adjusting for potential confounding factors. Adjusted odds ratios (OR) and 95% confidence intervals will be presented. Conclusions: This study will show preliminary insights into the role of GM as a potential biomarker for neoadjuvant therapy efficacy in patients with GI cancers. Recruitment is on-going.